A variety of fungal infections can occur in patients due to pathogenic Candida or Aspergillus fungus species. Examples of such fungal infections include candidemia, candidiasis (including esophageal infections, abdominal infections, pleural space infections and peritoneal infections), and invasive aspergillosis. Early antifungal agents typically attacked the inner cell membrane of the invasive fungus. These early agents had a variety of drawbacks, however, including toxic side effects, drug-drug interactions, variations in efficacy between patients, and fungal resistance.
A more recent family of antifungal agents is the echniocandins, which treat fungal infections through a different mechanism—inhibition of the enzyme that forms β-(1,3)-D-glucan, an essential component of the fungal outer cell wall. Since β-(1,3)-D-glucan does not occur naturally in the cell walls of mammals, the action of echinocandins is unlikely to be harmful to the cells of an infected patient. Due to the difference in their mechanism of action relative to earlier agents, echinocandins have not experienced wide resistance by target fungi.
Caspofungin acetate was the first of the echinocandins to be approved in the U.S. for use as an antifungal agent. The full name for caspofungin acetate is reported as 1-[(4R,5S)-5-[(2-aminoethyl)amino]-N2-(10,12-dimethyl-1-oxotetradecyl)-4-hydroxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine]pneumocandin B0 diacetate (salt), and a representative chemical structure of caspofungin acetate is shown in FIG. 1. An approved treatment regimen for adults includes an initial administration of 70 milligrams (mg) caspofungin acetate, followed by daily administration of 50 mg caspofungin acetate, where each administration is performed through intravenous infusion over 1 hour.
As caspofungin acetate has poor oral bioavailability, it typically has been provided to medical personnel as a lyophilized solid, which is then reconstituted before intravenous administration to a patient. In one example, a formulation of caspofungin acetate that is commercially available at present is sold under the CANCIDAS® trademark. CANCIDAS® for Injection (Merck & Co, Inc.; Whitehouse Station, N.J., USA) is currently available as a lyophilized powder. CANCIDAS® is available in vials containing either 54.6 mg or 75.6 mg of caspofungin acetate, in combination with sucrose and mannitol, and including acetic acid and sodium hydroxide as pH modifiers. CANCIDAS® is reconstituted for administration by combining the lyophilized powder with 10.8 milliliters (mL) of a reconstitution liquid (such as 0.9% sodium chloride), to provide a solution having a caspofungin acetate concentration of either 7 milligrams per milliliter (mg/mL) or 5 mg/mL. This reconstituted liquid typically is diluted with an infusion liquid prior to administration.
One challenge associated with the commercially available formulation of caspofungin acetate is its instability, including its instability at ambient temperatures. Degradation products of caspofungin acetate at room temperature (˜25° C.) include various dimers of caspofungin, as well as other substances. Current protocols require caspofungin acetate to be stored at −70° C. (±10° C.), and require the lyophilized CANCIDAS® formulation to be stored at temperatures of 2-8° C. A reconstituted liquid formed from the CANCIDAS® formulation must be diluted within one hour, and then either administered within 24 hours or stored at 2-8° C. for up to 48 hours. These temperature and time constraints present potential difficulties for effective administration of caspofungin acetate, both in medical professional settings and in outpatient settings. See, for example, Tsiouris, Maria et al. “Stability and compatibility of reconstituted caspofungin in select elastomeric infusion devices”, International Journal of Pharmaceutical Compounding (2010), 14(5), 436-439.
Various reformulations have been reported to improve the stability of caspofungin. The use of the acetate salt form of caspofungin was an initial effort at improving the stability of caspofungin, as earlier versions of caspofungin formulations used the tartrate salt instead. Thus, the CANCIDAS® formulation, which includes caspofungin in its acetate salt form, has improved stability relative to formulations of caspofungin tartrate. See U.S. Pat. No. 5,952,300, column 2, lines 22-56 and column 8, lines 11-67.
In another example, the pH modifiers acetic acid and sodium hydroxide were eliminated from the CANCIDAS® formulation, and the resulting formulations had improved stability at ambient temperatures. Lyophilized formulations were more stable with respect to caspofungin at 25° C. for 12 weeks, and reconstituted solutions of the formulations were more stable with respect to the caspofungin at 25° C. for 2 days. See US 2009/0170753, paragraphs [0080], [0204]-[0207] and [0214]-[0217].
In another example, the sucrose and mannitol in the CANCIDAS® formulation were replaced with a non-reducing sugar such as trehalose, and the resulting formulations had improved stability at ambient temperatures. Lyophilized formulations containing trehalose more were stable with respect to caspofungin at 30° C. for up to 72 weeks, and at 40° C. for up to 24 weeks. See US 2010/0137197, paragraphs [0114]-[0119].
It is desirable to have caspofungin acetate formulations that can be stored as lyophilized solids without the need for control of the surrounding temperature. For example, it is desirable for a lyophilized formulation of caspofungin acetate to be stable at temperatures of 25° C. or higher for a period of from 6 months to 2 years. Preferably such stabilized formulations would be convenient to prepare, store, reconstitute and administer.